Abundant evidence suggests an early and insidious pathogenesis of AD. By the time individuals are in the earliest clinical stages of AD, they already exhibit significant neuronal loss in affected brain regions. While there are presently no proven treatments that delay the onset or prevent the progression of AD, many promising candidates have this potential and are being developed. Therefore it is vital to have antecedent biomarkers as well as biomarkers of the earliest clinical stage of AD in order to target individuals for entry into therapeutic trials and to monitor therapy. The proposed research will combine new and unbiased proteomic techniques with unique samples from animal models of AD and humans at the very earliest pathological and clinical stages of AD, to identify candidate biomarkers of very mild AD. Our hypothesis is that the initial clinical stage of AD is associated with changes in the CSF proteome that can be discovered with state of the art proteomics techniques. Three specific aims will be pursued: 1) Identification of candidate antecedent biomarkers and biomarkers of very mild AD by analyzing brain tissue and interstitial fluid from the PDAPP mouse model of AD; 2) Direct identification of candidate biomarkers of very mild AD using clinically characterized human CSF samples; 3) Further screening/validation of candidate biomarkers identified in Aims 1 and 2. [unreadable] [unreadable]